The Molecular Imaging Branch aims to exploit positron emission tomography (PET) as a radiotracer imaging technique for investigating neuropsychiatric disorders, such as autism, depression, addiction, schizophrenia and Alzheimer's disease (AD). Fundamental to this mission is the development of novel radioactive probes (radiotracers) that can be used with PET to measure changes in low level proteins in living human brain where these proteins may be involved in the progression of neuropsychiatric disorders. Such proteins include neuroreceptors, enzymes, and plaques within brain, and drug efflux transporters at the blood-brain barrier. PET is a uniquely powerful and sensitive imaging modality for such purposes when successfully coupled to the use of effective PET radiotracers. The chemical development of new biochemically specific radiotracers is the key to exploiting the full potential of PET in neuropsychiatric research. A successful PET radiotracer must satisfy a wide range of difficult-to-satisfy criteria and hence PET radiotracer development is a highly challenging scientific task. In fact, this research has some parallels with drug discovery in terms of required effort and risk - because of the need for radioligands to satisfy such a wide range of criteria. Moreover, the number of potentially interesting imaging targets (brain proteins) far exceeds the range of available and useful radiotracers. Within MIB, the PET Radiopharmaceutical Sciences Section places a concerted effort on all chemical and radiochemical aspects of PET radiotracer discovery. Our laboratories are equipped for medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These two very short-lived radioisotopes are available to us daily from the adjacent cyclotrons of the NIH Clinical Center (Chief: Dr. P. Herscovitch). Our Section interacts seamlessly with the Imaging Section of our Branch (Chief: Dr. R.B. Innis) for early evaluation of potential radiotracers in biological models and in animals. Subsequent PET research in human subjects is also performed in collaboration with the Imaging Section under Food and Drug Administration oversight through 'exploratory' or 'full' Investigational New Drug applications. We are currently developing PET radiotracers for several targets. These include TSPO, cannabinoid (CB1), histamine, oxytocin, and glutamate (NMDA, mGlu1, mGlu5)receptors, COX and PDE enzymes,P-gp and BCR efflux transporters, and tau fibril deposits. One radiotracer that we have developed for TSPO imaging (C-11PBR28) is now being applied to investigate brain inflammatory conditions in response to various neurological insults (e.g., stroke, epilepsy and neurodegeneration). This radiotracer appears to be useful as a biomarker for the transition from mild cognitive impairment to full-blown Alzheimer's disease (AD). Several other institutions are now working with C-11PBR28. An unexpected finding is that healthy human subjects, because of small genetic differences, carry one or both of two distinct forms of TSPO and that these interact differently with C-11PBR28, complicatimg the analysis of PET studies. Consequently, we seek to develop genetically insensitive TSPO radiotracers. One new radiotracer, C-11ER176, appears promising in this regard and will be evaluated in human subjects. We are also developing a new chemotype that may provide superior PET radiotracers for TSPO. In addition, we are developing radiotracers for other targets relevant to the study of neuroinflammation, such as the cyclooxygenase (COX) enzymes. Cannabis receptors are relevant to the study of addiction. We developed a new CB1 receptor radiotracer C-11SD5024 and compared this with others developed earlier. One of these, F-18FMMEP, showed brain changes in CB1 receptors in cannabis and ethanol abuse. mGlu5 receptor radiotracers also have interest for the study of addiction, as well as other disorders, notably Fragile, an autistic condition, and schizophrenia. We produced two new mGlu5 radiotracers(C-11SP203 and C-11FPEB)for comparative evaluation in human subjects. We also developed a promising radiotracer (F-18FIMX) for a very related receptor target, namely mGlu1, which will be evaluated in human subjects. NMDA is another protein acted upon by the important neurotransmitter, glutamate. We are assessing the feasibility of imaging 'working' NMDA receptors, primarily because of their suspected imoportance in schizophrenia. Several candidate radiotracers are developed and are now being evaluated in animals for this purpose. Drug efflux pumps at the blood-brain barrier (BBB) may be involved in conditions such as AD. P-gp and BCRP are the two most prevalent pumps at the BBB. Following our successful development of C-11dLop to study P-gp function, we are now developing a complementary radiotracer for the BCRP pump in collaboration with Drs. M. Goettesman and M. Hall (NCI). C-11dlop is in use for clinical research at NIH and elsewhere. In collaboration with Prof. Diaz-Arrastia and colleagues (Uniformed Services University of the Health Sciences, we are developing radiotracers for imaging the accumulation of neurofibrillary tangles (tau protein), which may underlie the development of neurodegenerative disorders, such as AD and traumatic brain injury. We are also collaboring with academia (Riken, Japan) and Pharma (Avid, USA) to evaluate their early radiotracers for this target in human subjects. PET radiotracers can provide important quantitative information on experimental theraputics for neuropsychiatric disorders, such as ability to cross the BBB and to engage with a target protein. In collaborations with academia and Pharma, we developed several radiotracers for this purpose. Some of these radiotracers are targetted at proteins that have not previously been imaged in living human brain, and may have eventual clinical research utility. We continue to advance our methodology for improved radiotracer development. Progress was made across several areas, including synthesis, radiolabeling methods, and the use of micro-reactors for radiochemistry research. Especially, we combined the use of microfluidics with new labeling strategies to expand our range of candidate F-18 labeled radiotracers. Sensitive mass spectrometry (LC-MS/MS) was introduced to measure radiotracer half-life and specific radioactivity, and is also being developed to measure radiotracer concentration in blood following intravenous administration,as is required to analyze PET experiemnts. LC-MS/MS avoids the demanding logistics associated with measuring fast-decaying radioactivity. Productive collaborations were established with external academic chemistry and medicinal chemistry laboratories, nationally and internationally, and also with pharmaceutical companies through Cooperative Research and Development Agreements and the Biomarker Consortium of the Foundation for NIH. Productive collaborations also exist with other centers working with PET and its associated radiochemistry and radiotracer development. The laboratory is active in training new scientists for this field at graduate and postdoctoral level. We produce some useful radiotracers that have been developed elsewhere for PET investigations in animal or human subjects e.g., C-11CUMI (for 5-HT1A receptor imaging), and C-11rolipram (for PDE4 enzyme imaging). Each PET experiment with any radiotracer requires a radiosynthesis of the radiotracer on the same day, and hence radiotracer production is a regular activity. About 300 productions are performed annually.